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  • 1
    Online Resource
    Online Resource
    MS-275 (Entinostat) Promotes Radio-Sensitivity in PAX3-FOXO1 Rhabdomyosarcoma Cells
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 19 ( 2021-10-01), p. 10671-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 19 ( 2021-10-01), p. 10671-
    Abstract: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic RMS is often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MS-275 reversibly hampered cell survival in vitro in FN-RMS RD (RASmut) and irreversibly in FP-RMS RH30 cell lines down-regulating cyclin A, B, and D1, up-regulating p21 and p27 and reducing ERKs activity, and c-Myc expression in RD and PI3K/Akt/mTOR activity and N-Myc expression in RH30 cells. Further, MS-275 and RT combination reduced colony formation ability of RH30 cells. In both cell lines, co-treatment increased DNA damage repair inhibition and reactive oxygen species formation, down-regulated NRF2, SOD, CAT and GPx4 anti-oxidant genes and improved RT ability to induce G2 growth arrest. MS-275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RT-unresponsive RH30 xenografts when combined with radiation. Thus, MS-275 could be considered as a radio-sensitizing agent for the treatment of intrinsically radio-resistant PAX3-FOXO1 RMS.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms221910671
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
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  • 2
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    Online Resource
    Sharing Circulating Micro-RNAs between Osteoporosis and Sarcopenia: A Systematic Review
    MDPI AG ; 2023
    In:  Life Vol. 13, No. 3 ( 2023-02-21), p. 602-
    Details
    In: Life, MDPI AG, Vol. 13, No. 3 ( 2023-02-21), p. 602-
    Abstract: Background: Osteosarcopenia, a combination of osteopenia/osteoporosis and sarcopenia, is a common condition among older adults. While numerous studies and meta-analyses have been conducted on osteoporosis biomarkers, biomarker utility in osteosarcopenia still lacks evidence. Here, we carried out a systematic review to explore and analyze the potential clinical of circulating microRNAs (miRs) shared between osteoporosis/osteopenia and sarcopenia. Methods: We performed a systematic review on PubMed, Scopus, and Embase for differentially expressed miRs (p-value 〈 0.05) in (i) osteoporosis and (ii) sarcopenia. Following screening for title and abstract and deduplication, 83 studies on osteoporosis and 11 on sarcopenia were identified for full-text screening. Full-text screening identified 54 studies on osteoporosis, 4 on sarcopenia, and 1 on both osteoporosis and sarcopenia. Results: A total of 69 miRs were identified for osteoporosis and 14 for sarcopenia. There were 9 shared miRs, with evidence of dysregulation (up- or down-regulation), in both osteoporosis and sarcopenia: miR-23a-3p, miR-29a, miR-93, miR-133a and b, miR-155, miR-206, miR-208, miR-222, and miR-328, with functions and targets implicated in the pathogenesis of osteosarcopenia. However, there was little agreement in the results across studies and insufficient data for miRs in sarcopenia, and only three miRs, miR-155, miR-206, and miR-328, showed the same direction of dysregulation (down-regulation) in both osteoporosis and sarcopenia. Additionally, for most identified miRs there has been no replication by more than one study, and this is particularly true for all miRs analyzed in sarcopenia. The study quality was typically rated intermediate/high risk of bias. The large heterogeneity of the studies made it impossible to perform a meta-analysis. Conclusions: The findings of this review are particularly novel, as miRs have not yet been explored in the context of osteosarcopenia. The dysregulation of miRs identified in this review may provide important clues to better understand the pathogenesis of osteosarcopenia, while also laying the foundations for further studies to lead to effective screening, monitoring, or treatment strategies.
    Type of Medium: Online Resource
    ISSN: 2075-1729
    URL: Article
    DOI: 10.3390/life13030602
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662250-6
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  • 3
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    Online Resource
    Translational Implications for Radiosensitizing Strategies in Rhabdomyosarcoma
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 21 ( 2022-10-31), p. 13281-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 21 ( 2022-10-31), p. 13281-
    Abstract: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and FN-RMS, often mutant in the RAS pathway. Risk stratifications of RMS patients determine different prognostic groups and related therapeutic treatment. Current multimodal therapeutic strategies involve surgery, chemotherapy (CHT) and radiotherapy (RT), but despite the deeper knowledge of response mechanisms underpinning CHT treatment and the technological improvements that characterize RT, local failures and recurrence frequently occur. This review sums up the RMS classification and the management of RMS patients, with special attention to RT treatment and possible radiosensitizing strategies for RMS tumors. Indeed, RMS radioresistance is a clinical problem and further studies aimed at dissecting radioresistant molecular mechanisms are needed to identify specific targets to hit, thus improving RT-induced cytotoxicity.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232113281
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
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  • 4
    Online Resource
    Online Resource
    Cannabidiol Determination on Peripheral Capillary Blood Using a Microsampling Method and Ultra-High-Performance Liquid Chromatography Tandem Mass Spectrometry with On-Line Sample Preparation
    MDPI AG ; 2020
    In:  Molecules Vol. 25, No. 16 ( 2020-08-08), p. 3608-
    Details
    In: Molecules, MDPI AG, Vol. 25, No. 16 ( 2020-08-08), p. 3608-
    Abstract: The aim of this work is to evaluate volumetric absorptive microsampling (VAMS) from capillary blood as an alternative strategy for therapeutic drug monitoring (TDM) in patients treated with the newly available GW-purified form of cannabidiol (Epidiolex®). A fast ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) coupled to an online sample preparation system analysis was carried out on a Thermo Scientific Ultimate 3000 LC system coupled to a TSQ Quantiva triple quadrupole for the quantification of cannabidiol (CBD) and, in addition, delta-9-tetrahydrocannabinol (Δ9-THC). After validation using European Medicine Agency (EMA) guidelines the method was applied to samples obtained by finger prick of five pediatric patients treated with Epidiolex® and the results were compared to those obtained from venous blood and plasma. The method is linear in the range of 1–800 µg/L for both CBD and THC with intra- and inter-day precisions ranging from 5% to 14% and accuracies from −13% to +14% starting from 30 µL of sample. Stability in VAMS is ensured for up to 4 weeks at 25 °C thus allowing simple delivery. There was no difference (p = 0.69) between concentrations of CBD measured from VAMS sampled from capillary or venous blood (range: 52.19–330.14 or 72.15–383.45 µg/L) and those obtained from plasma (range: 64.3–374.09 µg/L) The VAMS-LC-MS/MS method represents a valid alternative strategy for therapeutic drug monitoring of patients treated with Epidiolex®.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules25163608
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2008644-1
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  • 5
    Online Resource
    Online Resource
    DNMT3A and DNMT3B Targeting as an Effective Radiosensitizing Strategy in Embryonal Rhabdomyosarcoma
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 11 ( 2021-10-30), p. 2956-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 11 ( 2021-10-30), p. 2956-
    Abstract: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10112956
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2661518-6
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  • 6
    Online Resource
    Online Resource
    T2Bacteria and T2Resistance Assays in Critically Ill Patients with Sepsis or Septic Shock: A Descriptive Experience
    MDPI AG ; 2022
    In:  Antibiotics Vol. 11, No. 12 ( 2022-12-15), p. 1823-
    Details
    In: Antibiotics, MDPI AG, Vol. 11, No. 12 ( 2022-12-15), p. 1823-
    Abstract: The use of rapid molecular tests may anticipate the identification of causative agents and resistance determinants in the blood of critically ill patients with sepsis. From April to December 2021, all intensive care unit patients with sepsis or septic shock who were tested with the T2Bacteria and T2Resistance assays were included in a retrospective, single center study. The primary descriptive endpoints were results of rapid molecular tests and concomitant blood cultures. Overall, 38 combinations of T2Bacteria and T2Resistance tests were performed. One or more causative agent(s) were identified by the T2Bacteria assay in 26% of episodes (10/38), whereas negative and invalid results were obtained in 66% (25/38) and 8% (3/38) of episodes, respectively. The same pathogen detected by the T2Bacteria test grew from blood cultures in 30% of cases (3/10). One or more determinant(s) of resistance were identified by the T2Resistance assay in 11% of episodes (4/38). Changes in therapy based on T2Bacteria and/or T2Resistance results occurred in 21% of episodes (8/38). In conclusion, T2Bacteria/T2Resistance results can influence early treatment decisions in critically ill patients with sepsis or septic shock in real-life practice. Large, controlled studies remain necessary to confirm a favorable impact on patients’ outcomes and antimicrobial stewardship interventions.
    Type of Medium: Online Resource
    ISSN: 2079-6382
    URL: Article
    DOI: 10.3390/antibiotics11121823
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2681345-2
    SSG: 15,3
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  • 7
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    Online Resource
    Cardiac Contractility Modulation Therapy in Patients with Amyloid Cardiomyopathy and Heart Failure, Case Report, Review of the Biophysics of CCM Function, and AMY-CCM Registry Presentation
    MDPI AG ; 2023
    In:  Journal of Clinical Medicine Vol. 12, No. 3 ( 2023-02-02), p. 1184-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 12, No. 3 ( 2023-02-02), p. 1184-
    Abstract: Cardiac amyloidosis may result in an aggressive form of heart failure (HF). Cardiac contractility modulation (CCM) has been shown to be a concrete therapeutic option in patients with symptomatic HF, but there is no evidence of its application in patients with cardiac amyloidosis. We present the case of TTR amyloidosis, where CCM therapy proved to be effective. The patient had a history of multiple HF hospitalizations due to an established diagnosis of wild type TTR-Amyloidosis with significant cardiac involvement. Since he was highly symptomatic, except during continuous dobutamine and diuretic infusion, it was opted to pursue CCM therapy device implantation. At follow up, a significant improvement in clinical status was reported with an increase of EF, functional status (6 min walk test improved from zero meters at baseline, to 270 m at 1 month and to 460 m at 12 months), and a reduction in pulmonary pressures. One year after device implantation, no other HF hospital admission was needed. CCM therapy may be effective in this difficult clinical setting. The AMY-CCM Registry, which has just begun, will evaluate the efficacy of CCM in patients with HF and diagnosed TTR amyloidosis to bring new evidence on its potential impact as a therapeutic option.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm12031184
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662592-1
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  • 8
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    Online Resource
    Long-Term Neuroradiological and Clinical Evaluation of NBIA Patients Treated with a Deferiprone Based Iron-Chelation Therapy
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 15 ( 2022-08-03), p. 4524-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 15 ( 2022-08-03), p. 4524-
    Abstract: Neurodegeneration with brain iron accumulation (NBIA) comprises various rare clinical entities with brain iron overload as a common feature. Magnetic resonance imaging (MRI) allows diagnosis of this condition, and genetic molecular testing can confirm the diagnosis to better understand the intracellular damage mechanism involved. NBIA groups disorders include: pantothenate kinase-associated neurodegeneration (PKAN), mutations in the gene encoding pantothenate kinase 2 (PANK2); neuroferritinopathy, mutations in the calcium-independent phospholipase A2 gene (PLA2G6); aceruloplasminemia; and other subtypes with no specific clinical or MRI specific patterns identified. There is no causal therapy, and only symptom treatments are available for this condition. Promising strategies include the use of deferiprone (DFP), an orally administered bidentate iron chelator with the ability to pass through the blood–brain barrier. This is a prospective study analysis with a mean follow-up time of 5.5 ± 2.3 years (min–max: 2.4–9.6 years) to define DFP (15 mg/kg bid)’s efficacy and safety in the continuous treatment of 10 NBIA patients through clinical and neuroradiological evaluation. Our results show the progressive decrease in the cerebral accumulation of iron evaluated by MRI and a substantial stability of the overall clinical neurological picture without a significant correlation between clinical and radiological findings. Complete ferrochelation throughout the day appears to be of fundamental importance considering that oxidative damage is generated, above, all by non-transferrin-bound iron (NTBI); thus, we hypothesize that a (TID) administration regimen of DFP might better apply its chelating properties over 24 h with the aim to also obtain clinical improvement beyond the neuroradiological improvement.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11154524
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 9
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    Online Resource
    Multi-Omics Studies Unveil Extraciliary Functions of BBS10 and Show Metabolic Aberrations Underlying Renal Disease in Bardet–Biedl Syndrome
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 16 ( 2022-08-20), p. 9420-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 16 ( 2022-08-20), p. 9420-
    Abstract: Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the ’ciliopathy’ field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where Bbs10 was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms23169420
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 10
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    Integrating a UAV-Derived DEM in Object-Based Image Analysis Increases Habitat Classification Accuracy on Coral Reefs
    MDPI AG ; 2022
    In:  Remote Sensing Vol. 14, No. 19 ( 2022-10-09), p. 5017-
    Details
    In: Remote Sensing, MDPI AG, Vol. 14, No. 19 ( 2022-10-09), p. 5017-
    Abstract: Very shallow coral reefs ( 〈 5 m deep) are naturally exposed to strong sea surface temperature variations, UV radiation and other stressors exacerbated by climate change, raising great concern over their future. As such, accurate and ecologically informative coral reef maps are fundamental for their management and conservation. Since traditional mapping and monitoring methods fall short in very shallow habitats, shallow reefs are increasingly mapped with Unmanned Aerial Vehicles (UAVs). UAV imagery is commonly processed with Structure-from-Motion (SfM) to create orthomosaics and Digital Elevation Models (DEMs) spanning several hundred metres. Techniques to convert these SfM products into ecologically relevant habitat maps are still relatively underdeveloped. Here, we demonstrate that incorporating geomorphometric variables (derived from the DEM) in addition to spectral information (derived from the orthomosaic) can greatly enhance the accuracy of automatic habitat classification. Therefore, we mapped three very shallow reef areas off KAUST on the Saudi Arabian Red Sea coast with an RTK-ready UAV. Imagery was processed with SfM and classified through object-based image analysis (OBIA). Within our OBIA workflow, we observed overall accuracy increases of up to 11% when training a Random Forest classifier on both spectral and geomorphometric variables as opposed to traditional methods that only use spectral information. Our work highlights the potential of incorporating a UAV’s DEM in OBIA for benthic habitat mapping, a promising but still scarcely exploited asset.
    Type of Medium: Online Resource
    ISSN: 2072-4292
    URL: Article
    DOI: 10.3390/rs14195017
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2513863-7
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